CN102378574B - 取代的偶氮蒽衍生物、药物组合物及其使用方法 - Google Patents

取代的偶氮蒽衍生物、药物组合物及其使用方法 Download PDF

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Publication number: CN102378574B
Authority: CN; China
Prior art keywords: phenyl; base; compound; carbonyl; dimethyl
Prior art date: 2009-03-30
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Active

Application number

CN2010800152644A

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English (en)

Chinese (zh)

Other versions

CN102378574A (zh

Inventor

A·M·M·米贾里

C·贝梅

D·P·克里森

D·R·波里塞蒂

J·奎达

K·桑索施

M·邦德拉

M·居泽尔

R·R·亚拉冈塔

D·R·戈希姆库拉

R·C·安德鲁斯

S·T·戴维斯

T·S·约库姆

J·L·R·弗里曼

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

vTv Therapeutics LLC

Original Assignee

vTvx Holdings I LLC

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2009-03-30

Filing date

2010-03-30

Publication date

2013-11-20

2010-03-30 Application filed by vTvx Holdings I LLC filed Critical vTvx Holdings I LLC

2012-03-14 Publication of CN102378574A publication Critical patent/CN102378574A/zh

2013-11-20 Application granted granted Critical

2013-11-20 Publication of CN102378574B publication Critical patent/CN102378574B/zh

Status Active legal-status Critical Current

2030-03-30 Anticipated expiration legal-status Critical

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HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 claims 36
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210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 claims 1
UODMTJPWTRAUQR-UHFFFAOYSA-N cyclohexyl hypochlorite Chemical compound ClOC1CCCCC1 UODMTJPWTRAUQR-UHFFFAOYSA-N 0.000 claims 1
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125000004129 indan-1-yl group Chemical group [H]C1=C([H])C([H])=C2C(=C1[H])C([H])([H])C([H])([H])C2([H])* 0.000 description 1
125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 description 1
125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
150000002475 indoles Chemical class 0.000 description 1
238000002347 injection Methods 0.000 description 1
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229910017053 inorganic salt Inorganic materials 0.000 description 1
239000004026 insulin derivative Substances 0.000 description 1
238000012739 integrated shape imaging system Methods 0.000 description 1
210000000936 intestine Anatomy 0.000 description 1
JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
150000002576 ketones Chemical class 0.000 description 1
210000003734 kidney Anatomy 0.000 description 1
230000037356 lipid metabolism Effects 0.000 description 1
239000012280 lithium aluminium hydride Substances 0.000 description 1
DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
238000004949 mass spectrometry Methods 0.000 description 1
208000030159 metabolic disease Diseases 0.000 description 1
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QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
OOVDEPZODSXAMU-MERQFXBCSA-N methyl (2s)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@](C)(N)CC1=CC=C(O)C=C1 OOVDEPZODSXAMU-MERQFXBCSA-N 0.000 description 1
YNTJMRFPJOFPBB-UTLKBRERSA-N methyl (2s)-2-amino-3-(4-pyridin-3-ylphenyl)propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=CN=C1 YNTJMRFPJOFPBB-UTLKBRERSA-N 0.000 description 1
KUYHWWRTSRRQBZ-AWEZNQCLSA-N methyl (2s)-2-amino-3-(4-pyridin-4-ylphenyl)propanoate Chemical compound C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC=C1 KUYHWWRTSRRQBZ-AWEZNQCLSA-N 0.000 description 1
PIUNBHWGWRIUQG-LTCKWSDVSA-N methyl (2s)-2-amino-3-(4-pyrimidin-4-ylphenyl)propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC=N1 PIUNBHWGWRIUQG-LTCKWSDVSA-N 0.000 description 1
BOFVVYUFGLYKPK-ZOWNYOTGSA-N methyl (2s)-2-amino-3-[4-(2,5-dimethylpyrazol-3-yl)phenyl]propanoate;hydrochloride Chemical compound Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC(C)=NN1C BOFVVYUFGLYKPK-ZOWNYOTGSA-N 0.000 description 1
KZJUKZLKCIDTJH-SQKCAUCHSA-N methyl (2s)-2-amino-3-[4-(2,5-dimethylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC(C)=NC=C1C KZJUKZLKCIDTJH-SQKCAUCHSA-N 0.000 description 1
WFIWHWIZKZQLQS-SQKCAUCHSA-N methyl (2s)-2-amino-3-[4-(2,6-dimethylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC(C)=NC(C)=C1 WFIWHWIZKZQLQS-SQKCAUCHSA-N 0.000 description 1
ZOXHCJRTMIFOOK-GXKRWWSZSA-N methyl (2s)-2-amino-3-[4-(2-aminopyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(N)=C1 ZOXHCJRTMIFOOK-GXKRWWSZSA-N 0.000 description 1
MMRUERBYEIBSEU-LTCKWSDVSA-N methyl (2s)-2-amino-3-[4-(2-aminopyrimidin-5-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CN=C(N)N=C1 MMRUERBYEIBSEU-LTCKWSDVSA-N 0.000 description 1
FXKGJSZSGGMWLG-SQKCAUCHSA-N methyl (2s)-2-amino-3-[4-(2-ethylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=NC(CC)=CC(C=2C=CC(C[C@H](N)C(=O)OC)=CC=2)=C1 FXKGJSZSGGMWLG-SQKCAUCHSA-N 0.000 description 1
HBIVMGDVKRRTDK-LTCKWSDVSA-N methyl (2s)-2-amino-3-[4-(2-methylpyrazol-3-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NN1C HBIVMGDVKRRTDK-LTCKWSDVSA-N 0.000 description 1
QLEXCAHRRZTNCN-CKUXDGONSA-N methyl (2s)-2-amino-3-[4-(2-methylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(C)=C1 QLEXCAHRRZTNCN-CKUXDGONSA-N 0.000 description 1
HOFRMLCEWFGDSO-GXKRWWSZSA-N methyl (2s)-2-amino-3-[4-(2-oxo-1h-pyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(O)=C1 HOFRMLCEWFGDSO-GXKRWWSZSA-N 0.000 description 1
JTPMAMGFSDCWSW-SQKCAUCHSA-N methyl (2s)-2-amino-3-[4-(3-methylphenyl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=CC(C)=C1 JTPMAMGFSDCWSW-SQKCAUCHSA-N 0.000 description 1
CHHIPTRCZWLGBL-CKUXDGONSA-N methyl (2s)-2-amino-3-[4-(3-methylpyridin-4-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC=C1C CHHIPTRCZWLGBL-CKUXDGONSA-N 0.000 description 1
SWJBPEXDUCZVHQ-HNNXBMFYSA-N methyl (2s)-2-amino-3-[4-(4-chlorophenyl)phenyl]propanoate Chemical compound C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(Cl)C=C1 SWJBPEXDUCZVHQ-HNNXBMFYSA-N 0.000 description 1
FWBUCIPBENKDCL-GXKRWWSZSA-N methyl (2s)-2-amino-3-[4-(6-aminopyridin-3-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(N)N=C1 FWBUCIPBENKDCL-GXKRWWSZSA-N 0.000 description 1
UZQNTNOCMBHTHJ-CKUXDGONSA-N methyl (2s)-2-amino-3-[4-(6-methylpyridin-3-yl)phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(C)N=C1 UZQNTNOCMBHTHJ-CKUXDGONSA-N 0.000 description 1
MLILKESKEVNHKE-CKUXDGONSA-N methyl (2s)-2-amino-3-[4-[2-(hydroxymethyl)pyridin-4-yl]phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(CO)=C1 MLILKESKEVNHKE-CKUXDGONSA-N 0.000 description 1
WNBCFEWMVAWWRM-GXKRWWSZSA-N methyl (2s)-2-amino-3-[4-[2-(trifluoromethyl)pyridin-4-yl]phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=NC(C(F)(F)F)=C1 WNBCFEWMVAWWRM-GXKRWWSZSA-N 0.000 description 1
HRJQWRTUPVHRBT-RSAXXLAASA-N methyl (2s)-2-amino-3-[4-[4-(trifluoromethyl)phenyl]phenyl]propanoate;hydrochloride Chemical compound Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(C(F)(F)F)C=C1 HRJQWRTUPVHRBT-RSAXXLAASA-N 0.000 description 1
GJKXBQRPEONFLG-CKUXDGONSA-N methyl (2s)-2-amino-3-[4-[6-(dimethylamino)pyridin-3-yl]phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(N(C)C)N=C1 GJKXBQRPEONFLG-CKUXDGONSA-N 0.000 description 1
HTGCHTIDQKPGIA-CKUXDGONSA-N methyl (2s)-2-amino-3-[4-[6-(hydroxymethyl)pyridin-3-yl]phenyl]propanoate;dihydrochloride Chemical compound Cl.Cl.C1=CC(C[C@H](N)C(=O)OC)=CC=C1C1=CC=C(CO)N=C1 HTGCHTIDQKPGIA-CKUXDGONSA-N 0.000 description 1
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NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D491/06—Peri-condensed systems

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Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CN102378574B (zh)	2009-03-30	2013-11-20	转化技术制药公司	取代的偶氮蒽衍生物、药物组合物及其使用方法
CN103030646B (zh) *	2011-09-29	2016-08-24	上海恒瑞医药有限公司	苯并二氧六环类衍生物、其制备方法及其在医药上的应用
CA2850987C (en)	2011-10-17	2019-10-15	Biotheryx, Inc.	Substituted biaryl alkyl amides
MX366685B (es) *	2013-01-17	2019-07-19	Vtv Therapeutics Llc	Combinaciones de un agonista de glp1r y metformina, y uso de los mismos para el tratamiento de la diabetes tipo 2 y otros trastornos.
WO2016033105A1 (en)	2014-08-29	2016-03-03	The Board Of Regents Of The University Of Texas System	Novel capsazepine analogs for the treatment of cancer and other proliferative diseases
JOP20190060A1 (ar)	2016-09-26	2019-03-26	Chugai Pharmaceutical Co Ltd	مشتق بيرازولو بيريدين له تأثير مساعد لمستقبل glp-1
TW201925204A (zh) *	2017-11-22	2019-07-01	日商第一三共股份有限公司	稠合三環化合物
JP7461104B2 (ja) *	2017-11-29	2024-04-03	中外製薬株式会社	Ｇｌｐ－１受容体アゴニスト作用を持つピラゾロピリジン誘導体を含有する医薬組成物
KR20210005843A (ko)	2018-05-08	2021-01-15	브이티브이 테라퓨틱스 엘엘씨	Glp1r 작용제의 치료적 용도
TWI707683B (zh) *	2018-06-13	2020-10-21	美商輝瑞股份有限公司	Ｇｌｐ－１受體促效劑及其用途
JP2023528726A (ja) *	2020-04-01	2023-07-06	ハンジョウジョンメイフアドンファーマシューティカルシーオー．，エルティーディー．	Ｇｌｐ１ｒアゴニスト遊離塩基の薬学的に許容される酸塩類およびその調製法
JP2023528565A (ja) *	2020-04-01	2023-07-05	ハンジョウジョンメイフアドンファーマシューティカルシーオー．，エルティーディー．	Ｇｌｐ－１受容体アゴニストの結晶形ａおよびその調製法
TW202144340A (zh)	2020-04-03	2021-12-01	大陸商江蘇恆瑞醫藥股份有限公司	稠合咪唑類衍生物、其製備方法及其在醫藥上的應用
TW202210462A (zh)	2020-05-28	2022-03-16	中國大陸商杭州中美華東製藥有限公司	（ｓ）－２－胺基－３－（４－（２，３－二甲基吡啶－４－基）苯基丙酸甲酯及其鹽的製備方法
WO2021242807A1 (en)	2020-05-28	2021-12-02	Vtv Therapeutics Llc	Methods for preparing methyl (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionate and hydrochloric acid salts thereof
US20230348412A1 (en) *	2020-05-28	2023-11-02	Hangzhou Zhongmei Huadong Pharmaceutical Co., Ltd.	Method for preparing glp-1 receptor agonist
CN115667219A (zh) *	2020-05-28	2023-01-31	杭州中美华东制药有限公司	一种(s)-2-氨基-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸甲酯二酸盐的制备方法
TW202210487A (zh)	2020-05-28	2022-03-16	中國大陸商杭州中美華東製藥有限公司	一種ｇｌｐ－１受體激動劑游離鹼的製備方法
WO2021242806A1 (en)	2020-05-28	2021-12-02	Vtv Therapeutics Llc	Intermediates and methods for preparing a glp-1 receptor agonist
US20230322756A1 (en)	2020-09-01	2023-10-12	Jiangsu Hengrui Medicine Co., Ltd.	Fused imidazole derivative, preparation method therefor, and medical use thereof
US20230382921A1 (en) *	2020-09-21	2023-11-30	Vtv Therapeutics Llc	Amorphous Form of Isoquinoline Derivative
WO2022076503A1 (en) *	2020-10-08	2022-04-14	Eli Lilly And Company	6-methoxy-3,4-dihydro-1h-isoquinoline compounds useful in the treatment of diabetes
WO2022078152A1 (zh)	2020-10-12	2022-04-21	杭州中美华东制药有限公司	苯并咪唑酮类glp-1受体激动剂及其用途
CN115461334A (zh)	2020-11-27	2022-12-09	深圳信立泰药业股份有限公司	一种苯并咪唑类衍生物及其制备方法和医药用途
EP4317142A1 (en)	2021-03-22	2024-02-07	Hangzhou Zhongmeihuadong Pharmaceutical Co., Ltd.	Thiophene glp-1 receptor agonist and use thereof
WO2022202864A1 (ja)	2021-03-24	2022-09-29	塩野義製薬株式会社	縮合環を有するｇｌｐ－１受容体作動薬を含有する医薬組成物
WO2022262615A1 (zh) *	2021-06-17	2022-12-22	杭州中美华东制药有限公司	蒽类化合物、其制备方法和医药用途
CN117500789A (zh) *	2021-06-17	2024-02-02	杭州中美华东制药有限公司	一种吡啶硼酸酯的制备方法
IL309235A (en)	2021-06-24	2024-02-01	Hangzhou Zhongmeihuadong Pharmaceutical Co Ltd	GLP-1 receptor agonist and its preparation and use
WO2023029979A1 (zh) *	2021-09-03	2023-03-09	杭州中美华东制药有限公司	Glp-1受体激动剂中间体的制备方法
WO2023038039A1 (ja)	2021-09-08	2023-03-16	塩野義製薬株式会社	抗肥満作用の関与する疾患の予防及び治療用医薬
CA3233453A1 (en)	2021-09-28	2023-04-06	Meimei Chen	Solid composition of glp-1 receptor agonist

Citations (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CN87100658A (zh) *	1986-02-11	1987-09-09	武田药品工业株式会社	1，4-苯并嗪类衍生物，它们的制备和应用
CN1658871A (zh) *	2001-12-21	2005-08-24	诺沃挪第克公司	作为gk活化剂的酰胺衍生物

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
BE795265A (fr) *	1972-02-09	1973-08-09	Philips Nv	Nouveaux derives de quinoleine a activite pharmacologique
US5756532A (en)	1995-11-06	1998-05-26	American Home Products Corporation	Aminomethyl-2 3 8 9-tetrahydro-7H-1 4-dioxino 2 3-E!-indol-8-ones and derivatives
EP1147094A1 (en) *	1999-01-15	2001-10-24	Novo Nordisk A/S	Non-peptide glp-1 agonists
CA2441790A1 (en)	2001-03-27	2002-10-03	Actelion Pharmaceuticals Ltd.	1,2,3,4-tetrahydroisoquinolines derivatives as urotensin ii receptor antagonists
ATE348828T1 (de)	2001-10-19	2007-01-15	Transtech Pharma Inc	Beta-carbolin-derivate als ptp-inhibitoren
JP4637089B2 (ja) *	2003-03-26	2011-02-23	アクテリオンファーマシューティカルズリミテッド	アセトアミド誘導体
WO2005014534A1 (en) *	2003-08-08	2005-02-17	Transtech Pharma, Inc.	Aryl and heteroaryl compounds, compositions, and methods of use
RU2284325C2 (ru)	2003-12-17	2006-09-27	Общество С Ограниченной Ответственностью "Асинэкс Медхим"	Производные фенил-3-аминометил-хинолона-2 в качестве ингибиторов no-синтетазы, способ их получения, биологически активные соединения и фармацевтическая композиция на их основе
WO2008118935A1 (en) *	2007-03-26	2008-10-02	Neurogen Corporation	Compounds and processes for preparing substituted aminomethyl-2,3,8,9-tetrahydro-7h-1,4-dioxino[2,3-e]indol-8-ones
MX2010009752A (es)	2008-03-07	2010-09-30	Transtech Pharma Inc	Compuestos de oxadiazoantraceno para el tratamiento de diabetes.
WO2009126709A1 (en)	2008-04-09	2009-10-15	Transtech Pharma, Inc.	Ligands for the glp-1 receptor and methods for discovery thereof
CN102378574B (zh)	2009-03-30	2013-11-20	转化技术制药公司	取代的偶氮蒽衍生物、药物组合物及其使用方法
US8501982B2 (en)	2010-06-09	2013-08-06	Receptos, Inc.	GLP-1 receptor stabilizers and modulators

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Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CN87100658A (zh) *	1986-02-11	1987-09-09	武田药品工业株式会社	1，4-苯并嗪类衍生物，它们的制备和应用
CN1658871A (zh) *	2001-12-21	2005-08-24	诺沃挪第克公司	作为gk活化剂的酰胺衍生物

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IL214822A0 (en)	2011-11-30
CA2757084C (en)	2017-08-29
CN102378574A (zh)	2012-03-14
WO2010114824A1 (en)	2010-10-07
US20150148539A1 (en)	2015-05-28
EP2413693B1 (en)	2015-09-09
JP5755217B2 (ja)	2015-07-29
EP2413693A1 (en)	2012-02-08
US8987295B2 (en)	2015-03-24
TN2011000437A1 (en)	2013-03-27
KR20120006506A (ko)	2012-01-18
MA33219B1 (fr)	2012-04-02
HK1164050A1 (en)	2012-09-21
US8383644B2 (en)	2013-02-26
EA201171197A1 (ru)	2012-04-30
SG174205A1 (en)	2011-10-28
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US9175003B2 (en)	2015-11-03
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BRPI1013579A2 (pt)	2020-11-03
WO2010114824A8 (en)	2011-10-06
EA023430B1 (ru)	2016-06-30
CA2757084A1 (en)	2010-10-07
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